iBet uBet web content aggregator. Adding the entire web to your favor.
iBet uBet web content aggregator. Adding the entire web to your favor.



Link to original content: http://pubmed.ncbi.nlm.nih.gov/37765334/
Effect of the Similarity of Formulations and Excipients of Approved Generic Drug Products on In Vivo Bioequivalence for Putative Biopharmaceutics Classification System Class III Drugs - PubMed Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2023 Sep 21;15(9):2366.
doi: 10.3390/pharmaceutics15092366.

Effect of the Similarity of Formulations and Excipients of Approved Generic Drug Products on In Vivo Bioequivalence for Putative Biopharmaceutics Classification System Class III Drugs

Ping Ren  1 , Theresa Chan  1 , Wen-Cheng Yang  1 , Mitchell Frost  1 , Yan Wang  1 , Markham Luke  1 , Myong-Jin Kim  1 , Robert Lionberger  1 , Yi Zhang  1
Affiliations

Effect of the Similarity of Formulations and Excipients of Approved Generic Drug Products on In Vivo Bioequivalence for Putative Biopharmaceutics Classification System Class III Drugs

Ping Ren et al. Pharmaceutics. .

Abstract

One of the potential essential factors that restricts generic industry from applying the Biopharmaceutics Classification System (BCS) Class III biowaiver is adherence to the stringent formulation criteria for formulation qualitative (Q1) sameness and quantitative (Q2) similarity. The present study has investigated formulations and excipients from 16 putative BCS Class III drug substances in a total of 19 drug products via 133 approved abbreviated new drug applications (ANDAs) containing in vivo bioequivalence (BE) studies in human subjects during the time period from 2006 to 2022. We included the BCS Class III drugs in this study by referring to published literature, the World Health Organization (WHO) BCS Class I-IV list, FDA internal assessments, and physicochemical properties (high solubility and low permeability) of specific drug substances. Based upon all 133 approved generic formulations in this study, the highest amount of each different compendial excipient with a total of 40 is defined as its corresponding typical amount that has not shown any potential impact on in vivo drug absorption. In the present study, although only 30.08% of the investigated generic formulations met Q1 the same/Q2 similar formulation criteria for the BCS Class III biowaiver, and while approximately 69.92% failed to meet those criteria with non-Q1/Q2 similar formulations, all test/reference ratios (T/R) and 90% confidence intervals for all instrumental PK parameters (AUC0-t, AUC0-inf, and Cmax) met the bioequivalence (BE) criteria (80-125%). The results of formulation assessment suggest that the commonly used excipients without atypical amounts did not impact absorption of 16 putative BCS Class III drug substances. The rate and extent of absorption of drugs appears to be more dependent upon the biopharmaceutic and physiochemical properties of BCS Class III drug substance and less, or not dependent upon their formulations, excipients, and the excipients class. Our findings may lead to a more flexible formulation design space regarding the stringent BCS Class III formulation criteria.

Keywords: Biopharmaceutics Classification System Class III; bioequivalence (BE); biowaiver; excipients; formulation; pharmacokinetic (PK); qualitatively (Q1)/quantitatively (Q2).

PubMed Disclaimer

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Distribution of diverse Q1 and Q2 formulations for in vivo BE studies. Approximately 30.08% of generic formulations were Q1/Q2 same or Q1 same/Q2 similar and 69.92% of generic drug formulations were non-Q1/Q2 similar.
Figure 2
Figure 2
Number of approved ANDAs exceeding BCS Class III-based biowaiver criteria on weight percentile changes (%w/w) with regard to different excipient class in four formulation groups: Q1 Different, Q1 Same/Q2 Different, Q1 Same/Q2 Similar, and Q1/Q2 Same.
Figure 3
Figure 3
Summary statistics of 217 BE studies under fasting and fed conditions using Box-and whisker plot for the distribution of the T/R ratios and 90% CIs of the T/R geometric mean ratios for Cmax, AUCt, and AUCinf by low or moderate permeability.
Figure 3
Figure 3
Summary statistics of 217 BE studies under fasting and fed conditions using Box-and whisker plot for the distribution of the T/R ratios and 90% CIs of the T/R geometric mean ratios for Cmax, AUCt, and AUCinf by low or moderate permeability.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

References

    1. U.S. Food and Drug Administration . The US FDA Guidance Documents, M9 Biopharmaceutics Classification System-Based Biowaivers. U.S. Food and Drug Administration; Silver Spring, MD, USA: 2021.
    1. Chen M.L., Straughn A.B., Sadrieh N., Meyer M., Faustino P.J., Ciavarella A.B., Meibohm B., Yates C.R., Hussain A.S. A modern view of excipient effects on bioequivalence: Case study of sorbitol. Pharm. Res. 2007;24:73–80. doi: 10.1007/s11095-006-9120-4. - DOI - PubMed
    1. Parr A., Hidalgo I.J., Bode C., Brown W., Yazdanian M., Gonzalez M.A., Sagawa K., Miller K., Jiang W., Stippler E.S. The Effect of Excipients on the Permeability of BCS Class III Compounds and Implications for Biowaivers. Pharm. Res. 2016;33:167–176. doi: 10.1007/s11095-015-1773-4. - DOI - PMC - PubMed
    1. Vaithianathan S., Haidar S.H., Zhang X., Jiang W., Avon C., Dowling T.C., Shao C., Kane M., Hoag S.W., Flasar M.H., et al. Effect of Common Excipients on the Oral Drug Absorption of Biopharmaceutics Classification System Class 3 Drugs Cimetidine and Acyclovir. J. Pharm. Sci. 2016;105:996–1005. doi: 10.1002/jps.24643. - DOI - PubMed
    1. Garcia-Arieta A., Gordon J., Potthast H. On the Effect of Common Excipients on the Oral Absorption of Class 3 Drugs. J. Pharm. Sci. 2016;105:1353–1354. doi: 10.1016/j.xphs.2016.01.005. - DOI - PubMed

Grants and funding

This research received no external funding.

LinkOut - more resources